This application is directed to phosphotriester derivatives of the drug molecule known as acyclovir (ACV) and their use as antiviral agents.
In prior patent application, PCT/FR93/00498 that published as WO93/24510, a very general approach that allows for intracellular delivery of mononucleotides using nucleosidic phosphotriesters bearing two bioreversible protecting groups was described by the present inventors.
It has now been found that this approach can be used for those nucleoside analogs which, in order to exert their biological activity, need to be phosphorylated into the corresponding triphosphates. Intracellular metabolization, such as phosphorylation, of nucleosides to active nucleotides requires the successive action of three kinases, the first one being highly selective and strongly regulated. As a consequence, if a nucleosidic analog is not phosphorylated by the first kinase, it cannot exert its inhibitory activity.
Some viruses, such as Herpes Simplex virus (HSV), encode for a vital kinase which is able to phosphorylate some nucleoside analogs that are not phosphorylated by cellular kinases. In particular, some acyclonucleosides which are not substrates for the first cellular kinase noted above do not show any activity against viruses which do not provide their own kinase. This is the case for the known antiviral drug, acyclovir (ACV), which has anti-herpetic activity due to its selective monophosphorylation by the thymidine kinase of Herpes Simplex virus. However, acyclovir has no activity against many other viruses, such as Human Immunodeficiency virus (HIV) or Hepatitis B virus (HBV), which do not provide the necessary viral kinases. Moreover, ACV is poorly active against those herpetic viruses in which thymidine kinase activity is either reduced or missing, such as Epstein-Barr virus or Cytomegalovirus. Further, it has been well established that acyclovir resistant Herpes Simplex viruses can appear both in vitro and in vivo, especially in highly immunodepressed patients. This resistance usually arises from a modification of the viral thymidine kinase, which results in a reduction or disappearance of the phosphorylation of ACV.
The intracellular delivery of acyclovir monophosphate (ACVMP) from various kinds of bioreversible phosphotriesters, as described in the patent application PCT/FR93/00498, is thus capable of enlarging the antiviral activity spectrum of this molecule.
In actuality, in comparison with ACV, phosphotriesters of ACV can be considered to be new therapeutic species since their activity spectrum is much larger than of ACV.
It is therefore an object of this invention to provide phosphotriester derivatives of acyclovir together with antiviral pharmaceutical formulations including such compounds.